Breast cancer is the second most common type of cancer worldwide (10.4%; after lung cancer) and the fifth most common cause of death by cancer (after lung cancer, stomach cancer, liver cancer, and colon cancer). Among women, breast cancer is the most common cause of death by cancer. In 2005, breast cancer caused 502,000 deaths worldwide (7% of the deaths by cancer; almost 1% of all deaths). The number of cases worldwide has increased significantly from the 1970s, a phenomenon which is partly due to the modern lifestyle in the western world.
Breast cancer is classified into stages according to the TNM system. The prognosis is closely related the results of the stage classification, and the stage classification is also used to assign patients to treatments both in clinical trials and in the medical practice. The information for classifying into stages is as follow:                TX: The primary tumor cannot be assessed. T0: there is no evidence of tumor. T is: in situ carcinoma, no invasion. T1 The tumor is 2 cm or less. T2 The tumor is more than 2 cm but less than 5 cm. T3: The tumor is more than 5 cm. T4: Tumor of any size growing in the wall of the breast or skin, or inflammatory breast cancer.        NX: The nearby lymph nodes cannot be assessed. N0: The cancer has not spread to the regional lymph nodes. N1: The cancer has spread to 1 to 3 axillary lymph nodes or to one internal mammary lymph node. N2: The cancer has spread to 4 to 9 axillary lymph nodes or to multiple internal mammary lymph nodes. N3: One of the followings applies:                    The cancer has spread to 10 or more axillary lymph nodes, or the cancer has spread to the infraclavicular lymph nodes, or the cancer has spread to the supraclavicular lymph nodes or the cancer affects the axillary lymph nodes and has spread to the internal mammary lymph nodes, or the cancer affects 4 or more axillary lymph nodes and minimum amounts of cancer are in the internal mammary nodes or in sentinel lymph node biopsy.                        MX: The presence of distant spread (metastasis) cannot be assessed. M0: There is no distant spread, M1: spreading to distant organs which do not include the supraclavicular lymph node has been produced.        
The fact that most of the patients with solid tumor cancer die after metastasis means that it is crucial to understand the molecular and cellular mechanisms allowing a tumor to metastasize. Recent publications have demonstrated how the metastasis is caused by means of complex yet little known mechanisms and also how the different metastatic cell types have a tropism towards specific organs. These tissue specific metastatic cells have a series of acquired functions allowing them to colonize specific organs.
All cells have receptors on their surface, in their cytoplasm and the cell nucleus. Certain chemical messengers such as hormones bind to said receptors and this causes changes in the cell. There are three significant receptors which may affect the breast cancer cells: estrogen receptor (ER), progesterone receptor (PR) and HER2/neu. For the purpose of naming the cells having any of these receptors, a positive sign is placed thereto when the receptor is present and a negative sign if it is absence: ER positive (ER+), ER negative (ER−), PR+(positive), PR negative (PR−), HER2+ (positive) and HER2 negative (HER2−). The receptor state has become a critical assessment for all breast cancers since it determines the suitability of using specific treatments, for example, tamoxifen or trastuzumab. The alpha isoform of the estrogen receptor (ER) is over-expressed in about 65% of the diagnosed cases of breast cancer. This type of breast cancer is referred to as “ER-positive” (ER+). In this case the binding of the estrogen to the ER stimulates the tumor mammary cell proliferation. The ER+ tumor cells are highly dependent on this stimulus to proliferate, therefore ER is currently used as a therapeutic target.
The keystone for treating breast cancer is surgery when the tumor is localized with possible adjuvant hormone therapy (with tamoxifen or an aromatase inhibitor), chemotherapy, and/or radiotherapy. Currently, the suggestions for treatment after the surgery (adjuvant therapy) follow a pattern. This pattern is subject to change because every two years, a world conference takes place in St. Gallen, Switzerland to discuss the actual results of the worldwide multi-center studies. Likewise, said pattern is also reviewed according to the consensus criterion of the National Institute of Health (NIH). Based on in these criteria, more than 85-90% of the patients not having metastasis in lymph nodes would be candidates to receive adjuvant systemic therapy.
Currently, PCR assays such as Oncotype DX or microarray assays such as MammaPrint can predict the risk of breast cancer relapse based on the expression of specific genes. In February 2007, the MammaPrint assay became the first breast cancer indicator in achieving official authorization from the Food and Drug Administration.
Patent application EP1961825-A1 describes a method for predicting the occurrence of breast cancer metastasis to bone, lung, liver or brain, which comprises determining in a tumor tissue sample the expression level of one or more markers with respect to their corresponding expression level in a control sample, among which include c-MAF. However, this document requires determining several genes simultaneously to enable determining the survival of breast cancer patients and the correlation between the capacity of the gene signature for predicting the survivability free from bone metastasis was not statistically significant.
Bos, P. D., et al. [Nature, 2009, 459:1005-1009] describes genes involved in the breast cancer metastasis to the brain.
Patent application US2005/0181375 describes methods for the detecting metastatic breast cancer based on detecting the expression levels of a series of genes which are randomly regulated or downregulated in metastatic tumors and particularly in tumors metastasizing to the brain.
International patent application WO2010/000907 describes a gene signature useful as genomic predictor for distal metastasis in breast cancer patients.
However, there are no genetic markers, in the state of the art, which allow the diagnosis and/or the prognosis of whether a patient who suffers a specific breast cancer, such as ER− or ER+ breast cancer, will or will not suffer metastasis, thus a suitable therapy being able to be applied to the subject suffering said cancer. Therefore, there is the need of identifying new markers which allow diagnosing the presence of metastasis in subjects suffering ER+ or ER− breast cancer and/or predicting the probability of a subject suffering ER+ or ER− breast cancer to develop metastasis. The identification of new prognosis factors will serve as a guide in selecting the most suitable treatments.